Spinal cord injury (SCI) is a devastating trauma; it results in lifelong permanent neurologic deficits/disabilities. About 10,000 new major spinal injuries occur in a year in the US, the largest part in car and sports accidents, affecting mostly young males. Unlike most injuries, which result in temporary tissue damage, spinal cord injuries result in permanent tissue rupture and consequent decay. The severed nerve fibers which normally transmit the messages from the brain to the cord fail to cross the wound gap, thus leaving the cord beyond the site of injury, disconnected from the brain. The nerve cells of the cord cannot function without the messages from the brain and the related muscles become and remain paralyzed.
Mechanical injury to the spinal cord not only tears the brain-cord nerve tracts, but it also ruptures the blood vessels [Allen (1911) J Amer Med Assoc. 57:878-880; Balentine (1978) Lab Invest. 39:236-253; Mautes et al. (2000) Phys Ther. 80:673-687]; and the integrity of the blood brain barrier (BBB), which separates the central nervous system (brain and spinal cord) from the systemic blood circulation, is broken [Runge et al (1997) Invest Radiol. 32:105-110; Jaeger & Blight (1997) Exp Neurol. 144:381-399; Mautes et al. (2000) Phys Ther. 80:673-687].
It appears that the wound-repair mechanism in the spinal cord is defective [Kalderon & Fuks (1996) Proc. Natl. Acad. Sci., USA 93:11179-11184]; revascularization at the lesion is abnormal and the cord-blood barrier function is compromised [Loy et al. (2002) J Comp Neurol. 445:308-324; Popovich et al. (1996) Exp Neurol. 142:258-275; Jaeger & Blight (1997) Exp Neurol. 144:381-399]. At present it is believed that the injury to the blood vessels results in ongoing secondary damage processes that lead to progressive tissue decay at the lesion site [Tator & Fehlings (1991) J Neurosurg. 75:15-26; Tator & Koyanagi (1997) J Neurosurg. 86:483-492; Mautes et al. (2000) Phys Ther. 80:673-687]. A perplexing issue is whether inflammatory processes are good or bad in the pathologic outcome of SCI, as some report beneficial whereas others point to harming effects [Mautes et al. (2000) Phys Ther. 80:673-687].
In most cases of SCI the tissue and/or brain-cord fibers are not completely severed; nevertheless, neurologic function below the damage site is permanently lost. It has been believed that the loss of function in the intact/spared fibers is due to the secondary damage processes. It has been assumed that inflammatory processes leads, among other decay processes, to demyelination, loss of the insulating sheath of the nerve fibers that conduct messages from the brain to the cord [Blight (1991) J Neuro. Sci. 106:158-174; Blight (1993) Adv Neurol. 59:91-104; Kakulas (1999) J Spinal Cord Med. 22:119-124]. This loss of myelin results in loss of electrical insulation and in the “short-circuiting” of the electrical signals traveling along the affected nerve fibers with loss of neurological activity. Recent results in a rat contusion injury model show demyelination and death of oligodendrocytes, the cells that make the myelin sheath [Beattie et al. (2000) J Neurotrauma 17:915-925].
The working hypothesis that led to this invention is that the breakdown of the blood-cord barrier following SCI leads to chronic inflammation which is the culprit in SCI pathology. Normal wound-repair mechanisms require for the initial limited period the participation of inflammatory processes; however, persisting inflammation inevitably results in serious pathologic consequences. We have shown in longitudinal studies that the onset of chronic inflammation occurs during the 3rd week after SCI in a rat model: ex vivo by histology [Kalderon & Fuks (1996) Proc. Natl. Acad. Sci., USA 93:11179-11184] and in vivo by magnetic resonance imaging (MRI) [Xu et al., Soc. Neurosci. Abstr. (1999) 25:493; Xu et al. (2000) Exp. Neurol. 163:295; Xu et al., Soc. Neurosci. Abstr. (2001) 27:2118; Murugandham et al., Proc Intl Soc Mag Reson Med (2002) 10]. It is assumed that the loss of function in the intact/spared fibers is due to the secondary damage caused by the chronic inflammation which is triggered at about the 3rd week after spinal cord injury.
Multiple sclerosis (MS) is a crippling neurodegenerative disease; it is an autoimmune disease in which the person's immune system attacks its own central nervous system (i.e., brain, spinal cord and optic nerve). MS is characterized by loss of the insulating myelin sheath from around the axons of the nerve cells. This loss of myelin results in loss of electrical insulation and the “short-circuiting” of the transmission of the electrical signals along the fibers of the affected nerves resulting in progressive neurological impairment; primarily progressive paralysis. Pathologically, these self-attacks can be detected in MRI scans as sites of BBB breakdown, inflammation and/or lesion [De Vries et al. (1997) Pharmacol Rev 49:143-155].
A modified form of beta interferon (Betaseron®) is the first drug shown to be effective in the treatment of relapsing-remitting multiple sclerosis. Beta interferon is one of a group of immune system proteins which are produced naturally by the human body. Interferons help to regulate the immune system, and beta interferon is thought to help slow down the immune system's attack on central neural tissue, which attack leads to chronic inflammation and demyelination.
One of the interferons, interferon beta-1b (Betaseron® was approved by the Food and Drug Administration (FDA) in 1993 for treatment of relapsing-remitting MS. It was found in a clinical trial to reduce the frequency and severity of exacerbations by approximately 30%. A second interferon, interferon beta-1a (Avonex®) has also been shown to reduce the frequency and severity of MS exacerbations in people with relapsing-remitting disease. Avonex® was approved for use in MS treatment in 1996.
While the ways in which Betaseron® actually affects MS are not clearly understood, it has been demonstrated clinically that it may decrease the nerve damage associated with MS. Betaseron® has been shown to reduce the overall frequency of MS relapses, which are also called exacerbations or attacks, including the number of moderate and severe relapses. In longitudinal MRI studies Betaseron® demonstrated a strong effect in reducing BBB breakdown, reducing sites/area of chronic inflammation and in reducing lesion frequency [Stone et al. Neurology. (1997) 49:862-869].
VCAM-1 on blood-brain barrier endothelium is one of the major mediators of leukocyte migration through the barrier during inflammation [Engelhardt et al. (1994) J Neuroimmunol. 51:199-208; De Vries et al. (1997) Pharmacol Rev 49:143-155; Risau et al. (1998) Patol Biol. (Paris) 46:171-175]. Recent data in an experimental animal, in a rat MS model, suggest that beta interferon directly modulates inflammatory events at the level of cerebral endothelium [Floris et al., J. Neuroimmun. (2002) 127: 69-79]. It was demonstrated in that study that beta interferon treatment resulted in a marked reduction of perivascular infiltrates; this was coupled to a major decrease in the expression of the adhesion molecules ICAM-1 and VCAM-1 in brain capillaries. Further, monocyte adhesion and subsequent migration were found to be predominantly regulated by VCAM-1. These data indicate that beta interferon exerts direct anti-inflammatory effects on brain endothelial cells, thereby contributing to reduced lesion formation as observed in MS patients.
No therapies are currently available for the primary damage in spinal cord injury. Only very limited therapeutic means are currently available for spinal cord injury treatment; these are aimed at reducing the degree/extent of the secondary damage during the very early acute phases following SCI. In fact, the only generally accepted acute intervention after SCI is administration within 8 hours after injury of high doses of the steroid methylprednisolone (MP) [Bracken et al. (1990) New Engl J Med. 322:1405-1411; Bracken (2000) J Neurosurg. 93:175-179]. However, after 13 years of experience this treatment is still quite controversial, and several recent studies suggest that treatment with MP may actually be contraindicated [Hurlbert (2000) J Neurosurg. 93:1-7; Pointillart et al. (2000) Spinal Cord 38:71-6].
No therapies are currently available for either the primary or the secondary damage in chronic SCI. Also, preclinical and clinical studies and published inventions and applications for inventions that are focused on development of therapies and interventions for SCI are devoted exclusively on the early phases, within several hours up to about a week, after SCI [for example, US patent application 20030027755, published Feb. 6, 2003].
Our preliminary data, in a rat spinal cord contusion injury model, show that chronic inflammation at the lesion site is triggered, at the molecular level, only by the end of the 2nd and/or 3rd week after injury. Our data show that following injury the expression of VCAM-1 on cord endothelial cells starts to increase above background levels only by the end of the 2nd week and/or 3rd week and that it becomes expansive throughout the lesion site by the 4th week postinjury [Burrows, et al., (2002) Program No. 133.10., 2002 Abstract Viewer/Itinerary Planner. Washington, D.C.: Society for Neuroscience, Online]. Based on our observations, it is anticipated that beta interferon would suppress the pathologic enhanced expression of VCAM-1 following spinal cord injury in the same manner it does in experimental models of MS. It is anticipated that beta interferon would gain access to the lesion site via the leaky BBB and would exert its physiological function, inhibiting thereby the chronic inflammation and demyelination and thus leading to rescue of neurologic function of the spared, uninjured spinal cord tissue including the spared brain-cord fiber tracts.